Eric Grigsby, MD, MBAneurovations.com/.../07/...Autoimmune-PPT-Full.pdfJul 07, 2020 · • Ann...
Transcript of Eric Grigsby, MD, MBAneurovations.com/.../07/...Autoimmune-PPT-Full.pdfJul 07, 2020 · • Ann...
Eric Grigsby, MD, MBA
David Chernoff, MD
Chief Medical OfficerSetpoint Medical
Patient Care & Innovation Since 1992
2010-11
N3
Laboratories
Neuromodulation: The Science
debuts focused on science and
innovation of neuromodulation.
Napa Pain Institute earns
conference accrediting rights
for continued medical
education which at multiple
conferences and events. N3
Laboratories is established.
1997-98
Clinical
Research
Leveraging Mayo Clinic
training, Dr. Grigsby
becomes Principal
Investigator in early
stage trials with active
involvement in clinical
and translational patient
care
1991-94
Napa Pain
Institute
Dr. Grigsby is certified in
first cohort of pain
management by the Board
of Anesthesiology.
2013-14
Spine and Pain
Center of Kaua’i
The Kauai Clinic is
established in part to
handle an underserved
clientele. Kauai Pain
Conference debuts to an
international audience.
1989-90
Inaugural
Napa Pain
Conference
Dr Grigsby starts one of
the first university pain
management clinics in
the US at UC Davis.
2005
Neurovations!
Research and education
combine to become
Neurovations-a patient
care and innovation
company .
2016
Redwood
Pain Institute
Redwood Pain Institute
opens in partnership with
St. Joseph’s Health.
2018-19
Neurovations
Center for Hope
The Neurovations Center
for Hope begins research
and development phase
with 5 patients.
Clinics which do clinical research
An innovation company which owns medical
services
Vagal Nerve Stimulation – Many Possibilities
Depression
Anxiety
Seizures
Autonomic dysfunction
Tinnitus
Constipation
Atrial fibrillation
Migraine
Weight loss
Rheumatoid Arthritis
Vagus Nerve Stimulation
• VNS - Implanted electrode and pulse generator
• tVNS - transdermal vagus nerve stimulation
• taVNS - transdermal, auricular, vagus nerve stimulation
VNS and Epilepsy
The Food and Drug Administration (FDA) has approved
vagus nerve stimulation for people who:
Are 4 years old and older
Have focal (partial) epilepsy
Have seizures that aren't well-controlled with medications
VNS and Depression
The FDA has also approved vagus nerve stimulation for the treatment of
depression in adults who:
• Have chronic, hard-to-treat depression (treatment-resistant depression)
• Haven't improved after trying four or more medications or ECT, or both
• Continue standard depression treatments along with vagus nerve stimulation
Covid and tVNS – Airway Effects
This week the Gammacore tVNS system was approved
by FDA under the EUA for:
“…adult patients with known or suspected COVID-19 who are experiencing
exacerbation of asthma-related dyspnea and reduced airflow….”
David Chernoff, MD
Chief Medical OfficerSetpoint Medical
16
DAVID CHERNOFF, MD
Chief Medical Officer
SetPoint Medical
Electrical Activation of Neural
Reflexes for Treatment of
Autoimmune Diseases
17
NEURAL CONTROL OVER INFLAMMATION
• Ann Rheum Dis 2004;63:1349-1351
18
THE INFLAMMATORY REFLEXDISCOVERY OF AFFERENT ARC
• Neurosci Lett 1995;183(1):27
Brain Stem
Vagus nerve
IL-1
Fever Response
19
THE INFLAMMATORY REFLEXMECHANISM OF ACTION MODULATES MULTIPLE INFLAMMATORY PATHWAYS
1. Neurosci Lett 1995;183(1):27
2. Nature 2000;405(6785):458
3. PNAS 2008;105(7):11008
4. J Exp Med 2006;203(7):1623
5. Science 2011;334(6052):98
6. Nature 2003;421(6921):385
7. Nat Immunol 2005;6(8):844
8. Nat Med 2004;10(11):1216
Afferent Arm: Increase in peripheral
mediators is sensed
Vagus Nerve
Stimulation
+
TNF
IL-6
IL-1
Celiac Plexus
1
2
2,7,8
3
4
5
6
Efferent Arm: (“Cholinergic anti-inflammatory
pathway”)
Mediator production is decreased
20
PRECLINICAL RESEARCH
• Arthritis
• Colitis
• Multiple Sclerosis
• Endotoxemia
• Sepsis
• Pancreatitis
• Hemorrhagic shock
• Intracerebral hemorrhage
• Ischemia-reperfusion
• Suprarenal aortic
• Myocardial
• Renal
• Cerebral
• Artery occlusion shock
• Carrageenan-induced inflammation
• Burn-induced injury
• Ventilator-induced lung injury
• Post-operative ileus
EXPERIMENTIAL INFLAMMATION MODELS USED TO CONFIRM THE MECHANISM OF ACTION FOR INFLAMMATORY REFLEX
• Bioelectronic Medicine, 1, 34-43 (2014)
• Immunol Rev. 248(1):188-204 (2012)
21
PRECLINICAL RESEARCHMANIPULATION OF THE INFLAMMATORY REFLEX IN COLLAGEN-INDUCED ARTHRITIS (CIA) MODEL
• Arth & Rheum 2009; 60:114
Vagotomy worsens CIA α7 nAChR KO Mice get more severe disease
Days after immunization
20 24 26 28 31 34 38 41 44
Clin
ical score
(m
ean
±S
EM
)
Wild Type
α7nAChR KO
Days after immunization
20 24 28 33 38 42 47
Clin
ical score
(m
ean±
SE
M)
22
PRECLINICAL RESEARCHNEUROSTIMULATION OF CHOLINERGIC ANTI-INFLAMMATORY PATHWAY IN RAT COLLAGEN-INDUCED ARTHRITIS (CIA) MODEL
• PLoS One 2014; 9(8):e104530
S tu d y D a y
An
kle
Dia
me
ter O
ve
r T
ime
(m
m)
9 1 0 1 1 1 2 1 3 1 4 1 5 1 6
6 .6 0
7 .0 0
7 .4 0
7 .8 0
8 .2 0
C o n tro l/N o Im p la n t
C IA /S h a m N C A P
C IA /N C A P
*
**
*
*
* * * **
An
kle
His
tolo
gy
Sc
ore
(0
-5);
Da
y 1
6
Inf l
am
mati
on
Pan
nu
s
Car t
ilag
e
Dam
ag
eB
on
e
Reso
rpt i
on
0
1
2
3
4
5
C IA /S h a m N C A P
C IA /N C A P
**
*
*
23
PRECLINICAL RESEARCHVAGUS NERVE STIMULATION IN RAT COLLAGEN-INDUCED ARTHRITIS (CIA) MODEL REDUCES KEY CIRCULATING PROINFLAMMATORY CYTOKINES
• PLoS One 2014; 9(8):e104530
24
TRANSLATIONAL RESEARCHBRIEF PERIODS OF ELECTRICAL VAGUS STIMULATION IN MICE INDUCED PROLONGED REDUCTION IN LPS-INDUCED TNF PRODUCTION
• Crit Care Med 2007; 35:2762
Implication: Therapeutic effect can likely be achieved chronically in humans
with low duty cycle stimulation
0 1 2 3
0
2 5
5 0
7 5
1 0 0
T im e (d a y s p o s t-V N S )
[Se
ru
m T
NF
] (%
Un
sti
mu
late
d)
* *
* *
* *
0
2 5
5 0
7 5
1 0 0
S tim u la tio n T im e (m in u te s )
[Se
ru
m T
NF
] (%
Un
sti
mu
late
d)
0 0 .5 2 2 0
* *
* * * *
30s VNS results in 48h TNF suppression
Minimal benefit observed when stimulation time increased
25
Could the cholinergic anti-inflammatory pathway
control chronic inflammation?
Koopman FA & Tak PP. J Int Med 2017;282:64-75
Vagus
nerve stimulation
Rheumatoid arthritis
Reduced inflammation
Andersson and Tracey J Exp Med
2012
Koopman et al. Proc Natl Acad Sci USA 2016
26
Vagal nerve stimulationCytokines
Pro-inflammatory eicosanoids
DAMPs
PAMPs
Pro-Resolving Mediators
Resolution
0
1
2
3
4
5
6
7
8
9
0 4 8 12 16 20 24 28 32 36 40 44 48 52
PM
N (
x 1
06)
Zy A
ZyA + Vagotomy
max
Ri
R50
Tmax T50
R50
T50
Time post challenge (h)
Inflammation + Vagotomy peritonitis
Inflammation
Pro-inflammatory Mediators
Kevin TraceyINFLAMMATORY REFLEX –
ANTI-INFLAMMATION
Vagotomy Delays Resolution and Reduces SPM
27
Circle size: amount of lipid mediators in the vagus nerve (pg/3.5cm) n=6
Human Vagus Nerve Produces Endogenous SPMs
28
Vagus nerve +Stimulation0
5
10
15
20
25
30
To
tal
Rv
(D3
, D4
, E1
) (p
g/m
l)
Vagus nerve +Stimulation0
3
6
9
12
153045
SP
Ms
(p
g/m
l)
Vagus nerve +Stimulation0
500
1000
1500
2000
To
tal
Pro
sta
no
ids
, Tx
B2 (p
g/m
l)
Vagus nerve +Stimulation0
200
400
600
800
1000
Pro
sta
no
ids
, T
xB
2 (p
g/m
l)
α
Results are express as mean ± SEM from three independent animals. *p<0.05.
Electrical Stimulation of Vagus Nerve Increases Endogenous
Production of SPMs and Reduces Prostaglandins
CN Serhan et al Cutting Edge J Immunol 2018
29
PRECLINICAL RESEARCHVAGUS NERVE STIMULATION AND IMMUNO-RESOLUTION
• Current Opinion in Immunology 2018, 50:48-54
30
CLINICAL RESEARCH – RA PROOF OF CONCEPTCOMMERCIALLY AVAILABLE VAGUS NERVE STIMULATOR (CYBERONICS) WAS EVALUATED WITH REPROGRAMMED PULSE PARAMETERS
Pulse Generator
Lead
31
CLINICAL RESEARCH – RA PROOF OF CONCEPT17 PATIENT, OPEN LABEL STUDY CONDUCTED IN EUROPE
4 centers; 12/17 patients from Academic Medical Center in AmsterdamCohort I: MTX-IR (7), Cohort II Multiple Biologic-IR (10)
Stimulation Parameters:
60s QD to QID
Average tolerated current was 1.22 and 1.60 mA in cohorts I and II, respectively
D
-21
5 weeks of VNS
Implant Screen
D
-14
D
0
D
7
D
14
D
21
D
28
D
42
D
56
D
84
Baseline Clinical Assessments Primary Endpoint
Single Intra-op stimulation
for diagnostic check
Transfer to long-term
follow up study
Single in-clinic stimulation at D0
biomarkers through D7Discontinue stimulation Restart stimulation
• PNAS 2016; 113(29): 8284.
32
CLINICAL RESEARCH – RA PROOF OF CONCEPT17-PATIENT EUROPEAN STUDY RESULTS DEMONSTRATE EARLY EFFICACY SIGNAL
LEGEND
Stimulation
Cohort 1- MTX IR + Biologic intolerant (7 Patients)
Cohort 2- 2+ MOA Biologic IR (10 Patients)
Combined Cohorts
Implant & Intraoperative Stimulation
Single In-Clinic Stimulation
Once-Per-Day Stimulation
Primary Endpoint | Stimulation Stopped
Resume Stimulation
1
2
3
4
5
STUDY WEEK
• PNAS 2016; 113(29): 8284.
33
CLINICAL RESEARCH – RA PROOF OF CONCEPTTNF KINETICS IN EX VIVO BIOASSAY PARALLELS CLINICAL ACTIVITY MEASURED BY DAS28-CRP
• PNAS 2016; 113(29): 8284.
34
CLINICAL RESEARCH – RA PROOF OF CONCEPTIMPROVEMENT IN DISEASE ACTIVITY MAINTAINED OVER 24 MONTHS
• All 17 subjects continued on active VNS treatment to 24 months of the long term follow-up study
DAS significant
Change
Primary Extension Study
0 6 1 2 1 8 2 4
-4
-3
-2
-1
0
S tu d y V is it M o n th
D
AS
28
-CR
P
-3 .5
35
CLINICAL RESEARCH – RA PROOF OF CONCEPTPATIENT IN LONG-TERM ”BOOLEAN” REMISSION
0 6 1 2 1 8 2 4
0
2
4
6
8
C o m b in e d S tu d y M o n th
DA
S2
8-C
RP
-3 .5
L o w D is e a s e
R e m is s io n
Primary Extension Study
Patient Medical History and Outcomes
Nationality Dutch
Gender Female
Years since diagnosis 18
Previous non-biologic DMARDsmethotrexate, sulfasalazine, leflunomide,
prednisone
Previous biologic DMARDs Etanercept, Adalimumab, Tocilizumab
RF factor, ACPA Seronegative
Measurement Baseline Month 24
hsCRP (mg/dL) 0.637 0.15
Baseline DAS28-CRP 5.79 1.35
Baseline CDAI 38.3 0.8
Tender/Swollen Joint Count 17 (T) / 6 (S) 0 (T) / 0 (S)
Patient Global Assessment 8/10 0.4/10 Boolean Remission: ≤ 1TJ/1SJ/1PGA/1CRP
36
• Integrated leadless system implanted via a
single incision
• Miniaturized, about an inch long; less than
2cc volume
• Rechargeable battery is inductively charged
and expected to last over 10 years
• MRI Conditional at 1.5T and 3.0T*
• Device is programmed to dose automatically
at patient’s therapeutic level, removing need
for patient compliance
SETPOINT MEDICAL SYSTEMINTEGRATED MICROREGULATOR
*The SetPoint System, specifically the MicroRegulator and POD, is MR Conditional. Scanning can be safely performed under the following conditions:
• Static magnetic field of 3 Tesla/128 MHz or less in a cylindrical-bore, horizontal field orientation, whole body coil (no transmitting local coils allowed, receiving local coils can be used),
• Maximum spatial gradient magnetic field of 720 Gauss/cm or less,
• MR system reported whole-body averaged specific absorption rate (SAR) of 2.9 W/kg for 15 minutes of scanning.
37
SETPOINT MEDICAL SYSTEMINTEGRATED SYSTEM DESIGNED TO MODULATE INFLAMMATORY REFLEX
Wireless ChargerMic roregulat or Pulse Generat or
iPad App
CHARGE
A f ew minut es
eac h week
IMPLANT
Along t he
vagus nerve
PRESCRIBE
HCP presc ribes
t herapy delivery
t hrough iPad app
38
CLINICAL RESEARCH - RA PILOT STUDY14 PATIENT U.S. STUDY TO EVALUATE SAFETY, PERFORMANCE AND SHAM EFFECT IN MULTI-BIOLOGIC REFRACTORY RHEUMATOID ARTHRITIS
KEY OBJECTIVES
• Safety and feasibility of SetPoint platform (Primary Endpoint)
• Confirmation of mechanism-of-action using cytokine analysis
• Assessment of clinical improvement and sham effect
Cohort 1
n = 3
Cohort 2
n = 11
Primary
EndpointOpen Label, Active VNS 1min QD
W
-6
W
-3
D
0W
4W
8
Baseline
Assessment 2 year
Extension
StudyW
12
Therapy Titration
Random
ized
Active VNS 1min QID
Active VNS 1min QD
Sham VNS
Device Implant
2+ MOA
Biologic IR
Patients
39
RA PILOT STUDY - BASELINE DEMOGRAPHICSMULTIBIOLOGIC AND JAKi REFRACTORY PATIENTS WITH SEVERE DISEASE ACTIVITY
SUBJECTTREATMENT
GROUP
YEARS
WITH RA
PRIOR bDMARD/
TARGETED SYNTHETICSGENDER
AGE
(YRS)
CDAI
(W -6)
DAS28-CRP
(W -6)RF/ACPA
005-01 Ph1 QD 49 4 F 66 45.5 5.55 +/+
005-03 Ph1 QD 13 4 F 47 22 4.20 -/-
006-01 Ph1 QD 24 5 F 46 58 7.06 +/+
002-01 Ph2 QD 6 4 F 26 41.5 7.04 +/+
005-06 Ph2 QD 3 2 M 73 29.5 4.47 -/+
005-07 Ph2 QD 17 10 F 45 43.5 6.79 +/+
Average QD 18.6 4.8 50.5 40 5.85
006-03 Ph2 QID 11 8 F 58 45.5 6.55 +/+
008-01 Ph2 QID 11 3 F 50 58 6.93 +/+
008-03 Ph2 QID 10 6 F 32 62 7.27 +/+
008-04 Ph2 QID 13 6 F 50 20 3.97 +/+
Average QID 11.2 5.8 47.5 46.4 6.18
005-05 Sham 10 4 F 66 53.5 6.75 +/+
006-02 Sham 15 4 M 44 29 4.42 +/+
006-04 Sham 16 3 F 53 24.5 4.45 +/+
008-02 Sham 4 3 M 57 64.5 7.64 +/+
Average Sham 10.8 3.8 55 42.6 5.82
Overall Study 14.25 4.8 50.9 42.6 5.94
• All subjects on background DMARDS (Methotrexate or Hydroxychloroquine)
• 9/14 patients had failed JAK inhibitors in addition to multiple biologics
40
RA PILOT STUDY: SUMMARY OF OUTCOMES
• Successfully implanted the device in 14 multi-biologic refractory RA patients ⎼ Device is safe and well tolerated; no device related adverse events
• SetPoint system performed as designed⎼ Device placement, communication between components, programmability, and delivery of stimulation occurred
as specified
• Pharmacodynamic response confirmed mechanism-of-action⎼ Reduction of proinflammatory cytokines was observed for QD and QID groups using validated biomarker assay
• Meaningful clinical response in treatment groups, with no apparent sham effect⎼ 5 out of 10 patients in treatment groups met or exceeded meaningful clinically important difference (MCID) in
DAS28-CRP at 12 weeks; ⎼ 2 patients achieved DAS28-CRP remission
⎼ Overall lack of DAS response in sham group
• Trends of joint structure preservation emerged in the MRI analysis⎼ Improvement in RAMRIS erosion scores correlated with DAS response; synovitis and osteitis scores were
inconclusive
STUDY MET PRIMARY ENDPOINTS WITH MEANINGFUL CLINICAL RESPONSE IN ACTIVE ARMS
41
RA PILOT STUDY - PHARMACODYNAMICSCYTOKINE ANALYSIS CONFIRM ACTIVATION OF INFLAMMATORY REFLEX IN STIMULATED COHORTS
• Validated immunoassay confirms reduction in proinflammatory cytokines for both treatment groups
• Biomarker analysis reaffirms mechanism-of-action observed in preclinical and European clinical studies
Mean Change with Standard Error
QD
QID
Sh
am
QD
QID
Sh
am
QD
QID
Sh
am
QD
QID
Sh
am
QD
QID
Sh
am
-75
-50
-25
0
25
50
% C
HA
NG
E F
RO
M B
AS
ELIN
E T
O W
EE
K12
IL-1 IL-6 IL-17 IL-23 TNF-
42
RA PILOT STUDY – CLINICAL RESPONSEMEANINGFUL CLINICAL IMPROVEMENT NOTED IN 50% OF ACTIVE GROUP NO OBSERVED SHAM EFFECT
QD QID Sham
-3
-2
-1
0
1
2
3
12-W
EE
K C
HA
NG
E IN
DA
S28-C
RP
DAS28
SIGNIFICANT
CHANGE
QD (6 Patients)
QID (4 Patients)
Sham (4 Patients)
LEGENDLEGEND
QD (n=6)
QID (n=4)
Sham (n=4)
43
PROPOSED PIVOTAL STUDY DESIGNRANDOMIZED, SHAM CONTROLLED, DOUBLE BLIND STUDY DESIGN
Treatment
Control
W
-6
W
-3
D
0
W
4
W
8W
16
W
20
M
6M
9
M
12
Primary
Endpoint
Active VNS
Sham VNS
Double blind period (12 weeks)
Assessment
Intervals W
12
Active VNS, QD 1 min
Patients
non-responsive/intolerant
to 1 or more Biologics
QD 1 min
W
14
Subjects eligible for rescue treatment
Implant
• Primary Endpoints:
• Improvement in clinical disease activity compared to sham at 12 weeks
• Safety, Secondary and Descriptive Endpoints:
• Safety of device via a description of all reported adverse events.
• Joint structure improvement, responder and remission rates, quality of life measures
n = 200
n = 100
n = 100
44
CONCLUSION AND DISCUSSION
• The inflammatory reflex is a prototypical cholinergic neuro-immune reflex that contributes to immunological homeostasis.
• Electrically stimulating the vagus nerve can activate this reflex therapeutically in many rodent models of disease, including rheumatoid arthritis
• Electrical stimulation of the vagus activates a proresolution of inflammation reflex
• Brief period of VNS was sufficient to induce a therapeutic response in half of patients with rheumatoid arthritis, many who had insufficient response to multiple biological drugs/JAKi
• Reduction of disease activity was sustained for at least two years in a substantial fraction of patients treated in EU study
• Upcoming clinical study designed to evaluate this therapy in a larger patient population with inadequate responses to biologics/JAKi
Questions?
William Bloor Professor of Theoretical Neuroscience Professor of Physiology and Cellular Biophysics Principal Investigator at Columbia’s Zuckerman Institute